1. Field of the Invention
The invention relates generally to intrauterine systems and in particular to devices that are capable of retaining and releasing a therapeutically effective dose of a biologically active compound within the uterus for treatment of a medical condition. The invention further relates to a method of manufacturing an intrauterine system having a biologically active compound deposited therein.
2. Description of the Related Art
The use of intrauterine devices (IUDs) has long been recognised as a convenient manner of providing long-term contraception. The presence of a device within the uterus causes the release of leukocytes and prostaglandins by the endometrium or uterine lining. These substances are hostile to both sperm and eggs and are understood to prevent fertilisation and any subsequent attachment of the fertilised egg to the endometrium. The use of copper in an IUD increases the spermicidal effect.
An IUD that has been widely accepted is presently marketed by N.V. Organon under the name Multiload™. Such a device is depicted in U.S. Pat. No. 3,952,734 and comprises an elongated stem carrying at one end two resilient, cantilevered arms, extending sideways on either side of the stem. A copper wire is wound about the stem. For insertion into the uterine cavity the stem is contained within a tube shaped sheath by means of which the device may be inserted through the cervix. The sheath narrowly encloses the stem and the shape and flexibility of the arms are chosen such that they can collapse around the sheath during insertion. The sheath may then be pulled back and the arms unfold to retain the IUD within the uterus. For the purpose of retrieval, a thread is attached to the stem at the opposite end from the arms. The thread extends through the cervix and can be pulled for removal of the device. Under normal circumstances the IUD may be effectively used for long periods of up to 5 years without removal.
More recently, devices have been developed that can include a quantity of a hormone for long term retention and release within the uterus. These devices are generally referred to as intrauterine systems (IUS) and the term IUS will be used hereafter to refer to IUDs having an incorporated agent. One system is marketed by Schering AG under the name Mirena™. The system comprises a T-shaped polyethylene frame with a steroid reservoir around the stem. The reservoir consists of a cylinder made of a mixture of levonogestrel and silicone. The reservoir is covered by a silicone membrane which controls the release rate to about 20 micrograms per day for a period of 3 to 5 years. Insertion and removal of the system is generally similar to that described above. Such a system is shown in U.S. Pat. No. 4,341,728. The use of steroids may enhance the contraceptive effect and also contribute to non-contraceptive health benefits (e.g. menorraghia) of the system. Copper coil type IUDs tend to increase bleeding during a woman's menstrual cycle. Using a hormone based IUS, menstrual bleeding may be reduced or even stop. Local administration of hormones also allows lower dosages to be used compared to other hormonal methods for contraception whose primary mode of action is suppression of ovarian function. Another device that uses a dose of a progestogen to augment the effect of a copper coil is shown in German patent DE 4125575 C. According to the document, the progestogen may be provided in crystalline form in the head of the IUD and its release rate controlled by diffusion through fine pores or a perforation. Alternatively, it may be mixed in a silicone-gelatine material or a rubber based material and applied externally to the IUD.
To effectively control the pharmacodynamic properties, a system must be able to store a sufficient dose of agent to ensure a sufficient flux over a prolonged period, yet small enough to prevent injury or pain on passing through the cervix. Another difficulty encountered in manufacturing an IUS is the need to produce a structure that is strong enough to endure the forces of insertion, removal and usage without breaking yet again is small enough to prevent injury or pain on passing through the cervix. In particular, the connection between the arms and the stem must be flexible to allow folding of the arms around or within the inserter. On removal the arms must again fold without breaking off, since loss of part of the device within the uterus could lead to complications. One device that attempts to solve these problems is shown in U.S. Pat. No. 7,080,647, in which arms are attached to a slot in a medicated fibre stem. The strength of the device appears to be dependent upon the limited material available for the slot connection. Another device is known from WO96/01092 in which a medicated deposit is used to form the arms of the device and the stem comprises a loop that encircles the arms.
A further difficulty lies in ensuring correct dosage of the agent. Prior devices use rate controlling membranes surrounding the agent. The need for integrity of the membrane has required complicated moulding procedures for connecting the body of the device to the agent deposit. EP1400258 and WO06/079709 describe solutions for manufacture of IUSs. A number of other IUSs are disclosed in which a quantity of agent is provided e.g. as a coating at an external surface of the device
Another alternative device is known from U.S. Pat. No. 3,656,483 which discloses a tubular body having perforations that allow for the release of a biologically active material. The material is in the form of a series of pellets that are biased towards the perforations by a spring member. Leaching of the medication takes place at the perforated region and the rate of release is controlled by the passage of the agent through the perforations. As each pellet is dissolved, the remaining pellets are pushed downwards by the spring. In this manner a series of different agents may be released successively. Nevertheless, the release rate of each agent is dependent upon the interrelation between the formulation and the perforations in the tubular body. Any blockages of the perforations would affect the subsequent release of the medication. The strength of the structure is provided by the external tube, which may make device insertion more difficult and painful.
An intrauterine system is disclosed in non-prepublished PCT application PCT/EP2008/065149 (and in the later published priority document EP 2057972) in which a deposit of a biologically active compound is retained within an open frame structure. The open structure of the frame allows the compound to be released at a rate that is believed to be substantially independent of the frame. The deposit may be in the form of a rod surrounded by a rate controlling membrane. A number of steroidal compounds having progestogenic activity are described, including a progestogen selected from the group consisting of nomegestrol acetate (NOMAc), natural progesterone, levonogestrel, etonogestrel, dydrogesterone, medrogestone, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, gestonorone caproate, demegestone, promegestone, nesterone, trimegestone, norethisterone (norethindrone), norethisterone acetate, lynestrenol, ethinodiol acetate, norethinodrel, norgestrel, norgestimate, dienogest, gestodene, and drospirenone. Values for etonogestrel loading are given within the range of 10-70% wt etonogestrel, preferably 30-65 wt % and more preferably 40-65 wt %. A specific example with a loading of 54 wt % etonogestrel is described. It is further described generically that intrauterine administration also represents a desirable route for many other medications and agents including hormone replacement agents, anti-cancer drugs, chemotherapeutic drugs, drugs to treat menstrual disorders and the like. The explicit content of this earlier application is hereby specifically disclaimed.
Intrauterine administration also represents a desirable route for many other medications and agents including hormone replacement agents, anti-cancer drugs, chemotherapeutic drugs, drugs to treat menstrual disorders and the like. It would be desirable to provide a device that could be easily adapted to one or more of these treatments with a minimum of device development.
It would be desirable to be able to manufacture a simple device in which the release rate of the medication or agent could be easily predicted for further compounds. The rate should also be reliably maintained in practice. Furthermore, the construction of the device should be simple and involve a minimum number of components and yet be both strong and flexible and small enough to allow easy insertion and correct removal.